This invention relates to medical devices that are resistant to bacterial growth or encrustation such as urological devices and more particularly to urinary catheters constructed of, or coated with, a material which enables the urinary catheters to inhibit urease, and to prevent calcium and magnesium phosphate deposits on the catheters.
Urinary catheters are used in urological surgery and when other methods of managing urinary incontinence fail. These catheters are generally made from a non-toxic, non-irritating material which is flexible but which will withstand collapse. Ideally they should resist colonization by bacteria and encrustation by mineral deposits. Short-term urological devices used to control incontinence such as the plastic urethral inserts suffer from susceptibility to bacterial adherence causing Urinary tract infection. (UTI).
The most common materials used for the catheters are latex, plastic or silicone. All biomaterials, including the most recently tested polyurethane, polyurethane-carbon and silicone-carbon, become encrusted with mineral deposits to varying extents. The degree of encrustation formation on biomaterials exposed to urine is dependent upon the biomaterial, the length of urinary exposure, the presence of infection and the solute content of urine. Several independent studies (e.g. Hukins et al., 1989) of the scraped encrusted material have identified--two major salts, namely apatite Ca.sub.5 (PO.sub.4).sub.3 (OH) and struvite Mg NH.sub.4 PO.sub.4 6H.sub.2 O. A very small amount of brushite CaHPO.sub.4.2H.sub.2 O has also been identified.
The pH increase of urine occurs due to urease producing bacteria, that infect the urine. Urease catalyzes the hydrolysis of urea at an enormous rate (10.sup.14 times as fast as the spontaneous hydrolysis of urea which is not observable in neutral solution) producing ammonia, which in turn precipitates calcium phosphates.
Microbial heterogeneity and structural complexity of the bio-films observed on infected catheter materials by means of scanning and transmission electron microscopy reveal a variety of microflora. It appears that the adherent microcolonies of bacteria are much less susceptible than their planktonic counterparts to antibiotics because the extensive anionic matrix surrounding the cell appears to comprise an ion exchange barrier between charged antibiotic molecules and their cellular targets. Antibiotics should be reserved for symptomatic, febrile infections; otherwise their use produces a change in bacterial flora with the potential for producing resistance.
Bacteriurea in a catheterized patient indicates the urinary tract has become colonized or infected. Administration of anti-bacterials such as nitrofurantoin, methenamine, and naldixic acid are used in practice. Most of these are not very effective in alkaline urine, and to achieve a high concentration in urine, the patient has to be given enormous doses.
Catheter associated Bacteriurea results from ascending bacterial colonization within glycocalyx enclosed biofilm on the inside and/or outside surfaces of the catheter and drainage systems. Urinary tract catheters made from a biomaterial that inhibits bacterial adherence and thus retards upstream colonization of bacteria may reduce acquired urinary tract infection (UTI). While hydrophilic surfaces show reduced protein adhesion, antibacterial surfaces offer better protection. Either a controlled release or an antibacterial immobilized on the surface should offer continuous protection against bacterial colonization. A silver oxide catheter is described in a publication by Shaeffer, A. J., Story, K. O., Johnson, S. M. in "Effect of silver oxide/Trichloroisocyanuric Acid Antimicrobial Urinary Drainage System on Catheter Associated Bacteriurea", J. Urol., 39, 60 (1988). A recent clinical study on silver catheters reported by Johnson, J. R., Roberts, P. L., Olsen, R. J., Moyer, K. A., and Stanni, W. E. in "Silver Oxide Coated Catheters", J. Infect. Diseases, 162, 1145 (1990) indicated the prevention of UTI among women not receiving antimicrobials.
The other problem associated with catheters left in place for long periods of time is the encrustation due to the formation of calcium hydroxyapatite and struvite. Long-term urethral catheterization is frequently necessary for patients with intractable urinary incontinence or retention. This procedure is employed in as many as 16-28% of patients in various chronic care facilities. More than 50% could suffer from blockage of their catheters. This can cause incontinence due to urinary bypassing of the catheter or acute pain and discomfort associated with urinary infection.
Removal of deposits by acidic solution (citric acid-magnesium oxide) has been shown to dissolve encrustation in vitro and is now used extensively in practice. Frequent irrigation could result in the damage of the mucus in the bladder.
A number of U.S. patents describe indwelling urinary catheter systems aimed at preventing urinary tract infection. These are mechanical devices with appropriate valve fittings to keep the drainage open while at the same time preventing ascending infection. U.S. Pat. Nos. 4,946,449 issued to Richard Davis and 4,878,901 issued to Hans Ernst Sachse are two typical examples. However, these do not have any prevention methods for encrustation. In general, mechanical systems are complicated and do not provide adequate protection from infection. U.S. Pat. No. 4,932,948 issued to Kernes et al., discloses the use of a funnel shaped insert at the end of the urinary catheter that serves as a reservoir to antimicrobial agents. The antimicrobial agent is simply mixed with the ethylene/vinyl acetate polymer during the fabrication of the funnel. The catheter surface itself does not carry any antimicrobial nor is it capable of preventing encrustation. U.S. Pat. No. 4,579,554 issued to Jacob Glassman discloses a design that provides for irrigation of the catheter tube. Frequent irrigation, however, could result in the damage of the mucus in the bladder.
U.S. Pat. No. 4,642,104 issued to Sakamoto et al. teaches the use of polymers carrying multicarboxyl, amino or sulfonic acid group capable of binding antibiotics through ion exchange. The ion exchange groups are chemically introduced into the molecules of the inside and outside wall of the urethral catheter by hydrolysis of certain functionalities that are present in the polymer that is coated on the surface of the catheter. Cationic antibiotics such as polymyxins or soap preparations such as benzalkonium chloride or benzethionium chloride, cyclohexidine or povidine-iodine remain on the surface due to the electrostatic binding. In order to introduce anionic groups on the surface of the catheter the surface has to be subjected to a series of chemical reactions and coatings, which could prove tedious and expensive.
U.S. Pat. No. 4,950,256 issued to Luther et al. teaches the use of an intravascular catheter comprising a cannula for insertion into a vascular system of a patient. This catheter is coated with a hydrophilic polyurethane-polyene composition for binding antithrombogenic materials and cationic polymyxin antibiotics. Luther et al., show that the absorption of the polymyxins into the hydrophilic polyurethane can be controlled by varying the initial concentrations, and the catheter is described as a time release intravascular catheter.
Amino phosphonates have been shown to prevent calcification of heart valves, and the process involves covalent bonding of the moieties to the biomaterial (C. L. Webb, et al., Trans. Am. Soc. Artif. Intern. Organs, XXXIV, 1851 1988!). Silver alloys (R. J. McLean et al., Can. J. Microbiol., 39 1993!; Liedberg and T. Lundberg, British Journal of Urology, 65, 379-381 1990!) have been reported to have been coated on urinary catheters and have been shown to be effective in preventing bacterial adherence.
The U.S. Pat. No. 5,295,979 teaches the use of two dissimilar metal coatings such as silver and platinum for creating an ionophoretic galvanic couple for driving silver ions in solution. This is achieved by sputtering a design of dots of the galvanic couple or by electroless plating of the successive metals.
Such coatings are hard to fabricate and require several manufacturing steps if multilayers are involved. The desired ratio of silver surface to volume for complete inhibition is about 25-50 square mm per mL of the growth medium. This is a difficult requirement to fulfill for a coating as the flow volumes are higher for urinary catheters.
The well publicized, ion-beam impregnated silver alloy catheters distributed by Spire Corporation do not provide protection in the lumen as the silver particles are embedded on the outside only. Also, these catheters do not protect against encrustation.
Recently, silver oxide coated Baxter catheters were clinically studied. The results showed that the catheters were not effective in preventing bacteriuria. Gram positive organisms were found to dominate (Riley et al., The American Journal of Medicine, 98, 349 1995!).
Polyethylene oxide coatings have been found to be bacteriostatic and protein-resistant (D. K. Han, S. Y. Jeong, and Y. H. Kim, et al., J. of Biomaterials Science, Polymer Edition, 4(6), 579-89 (1993) and the references therein). Such coatings do not have any antibacterial properties and have temporary anti adhesive properties. Biofilms eventually form on such coatings.
U.S. Pat. No. 5,328,954 issued to Sarangapani and assigned to the assignee of present application discloses a coating for medical applications which is resistant to encrustation and bacteria. While this coating is very effective for short term use when used on some materials, it is not as effective for long term uses. The coating uses high area carbon filler which emparts a blackish grey color to the coating. As a result, for the sake of cosmetic appearance colorants could not be used, while coating on latex or other white polymer devices.
It is therefore a principal object of the present invention to provide a catheter for use in urological surgery for long indwelling situations or for managing urinary incontinence which inhibits the build up of bacterial biofilm and encrustation on the surface of the catheter.
Another object of the present invention is to provide a catheter for use in urological surgery or provide materials for devices used for managing urinary incontinence which causes a lower risk of infection than known catheters.
Another object of this invention is to create an antibacterial surface by blending the additives such as organic acids, Silver and/or Platinum with a dissolved polymer, Titanium dioxide filler, or a prepolymer polyurethane followed by drying the solvent or by a direct melt blending method with the plastic.
Yet another object of this invention is to provide a combination of acidifying chelating compounds that partition between the plastic and the body fluids such as urine, to provide an acidic pH on the surface.